Purification of 2-nitro-4-methylsulphonylbenzoic acid

ABSTRACT

A method for removing impurities from 2-nitro-4-methylsulfonylbenzoic acid which comprises at least two of the following steps, in any order, (a) dissolving 2-nitro-4-methylsulfonylbenzoic acid in water at a pH of about 2 to 10, followed by filtration; (b) contacting an aqueous solution of 2-nitro-4-methylsulfonylbenizoic acid with activated carbon at a pH of about 2 to 10; (c) treating an aqueous solution of 2-nitro-4-methylsulfonylbenzoic acid with sufficient base to hydrolyze undesired nitro and dinitro substituted impurities; followed by maintaining the resulting aqueous solution comprising 2-nitro-4-methylsulfonylbenzoic acid at a temperature of up to about 95° C., and adjusting the pH of said solution to about a pH which is sufficient to effect crystallization of 2-nitro-4-methylsulfonylbenzoic acid upon cooling.

this application is a 371 of PCT/GB02/01433 issued Mar. 25, 2002 whichclaims benefit of Ser. No. 60/275,061 issued Mar. 26, 2001.

The present invention relates to a method for preparing high purity2-nitro-4-methylsulfonylbenzoic acid, to purified2-nitro-4-methylsulfonylbenzoic acid from the method, to a process formaking mesotrione using the purification method followed by furthersteps, and to mesotrione produced by this process.

Mesotrione (2-(4-methylsulfonyl-2-nitrobenzoyl)cyclohexane-1,3-dione) isa triketone compound useful as a corn herbicide for pre- andpost-emergence control of grass and broadleaf weeds:

Mesotrione can be manufactured by first reacting2-nitro-4-methylsulfonylbenzoic acid (NMSBA);

with phosgene in the presence of an organic solvent to provide thecorresponding acid chloride, i.e.,

The acid chloride intermediate can then be reacted with1,3-cyclohexanedione in the presence of a cyanide catalyst andtriethylamine to form crude Mesotrione. The solvents can be removed viadistillation and the Mesotrione precipitated from the remaining reactionmixture through a series of pH adjustment steps and isolated byfiltration or centrifugation.

We have found that mesotrione made by this process can give a positiveAmes test result. Surprisingly, we have discovered that this is not aninherent property of mesotrione, nor is it the result of by-productsfrom the reaction outlined above, but in fact results from impurities inthe NMSBA starting material. In an effort to overcome this problem andto provide Mesotrione product that exhibits a negative Ames testresponse, it would be desirable to develop a method for purifying thestarting material NMSBA, thereby removing these impurities.

Accordingly, the present invention provides a method for removingimpurities from 2-nitro-4-methylsulfonylbenzoic acid, which comprises atleast two of the following steps, in any order,

-   -   (a) dissolving 2-nitro-4-methylsulfonylbenzoic acid in water at        a pH of about 2 to 10, followed by filtration;    -   (b) contacting an aqueous solution of        2-nitro-4-methylsulfonylbenzoic acid with activated carbon at a        pH of about 2 to 10;    -   (c) treating an aqueous solution of        2-nitro-4-methylsulfonylbenzoic acid with sufficient base to        hydrolyze undesired nitro and dinitro substituted impurities;        followed by maintaining the resulting aqueous solution        comprising 2-nitro-4-methylsulfonylbenzoic acid at a temperature        of up to about 95° C., and adjusting the pH of said solution to        a pH which is sufficient to effect crystallization of        2-nitro-4-methylsulfonylbenzoic acid upon cooling. Preferably,        the pH is adjusted to about 1 prior to cooling and        crystallization.

By means of the invention, it is possible to remove impurities typicallyfound in 2-nitro-4-methylsulfonylbenzoic acid which, we have discovered,tend to give a positive Ames test result in the final Mesotrioneproduct.

To maintain the temperature of the resulting solution comprising2-nitro-4-methylsulfonylbenzoic acid, typically said solution is heated;however, it is possible that the reaction will be at a sufficienttemperature so that heating will not be required. The temperature istypically maintained between about ambient and about 95° C., preferablybetween about 85° C. and about 95° C.

In the method of the invention it is preferred wherein steps (a) and (b)are utilized, wherein steps (a) and (c) are utilized, wherein steps (b)and (c) are utilized, wherein steps (a), (b) and (c) are utilized, orespecially wherein steps (a), (b) and (c) are utilized in order.

The method of the invention preferably further comprises the step ofwashing said crystalline 2-nitro-4-methylsulfonylbenzoic acid withsolvent, and optionally drying said crystalline2-nitro-4-methylsulfonylbenzoic acid.

It is also preferred wherein in step (a) the pH is adjusted to about 3to 7.

In step (a), the base is preferably selected from the group consistingof potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodiumcarbonate, and sodium bicarbonate.

It is further preferred wherein in step (b) the activated carbon is inthe form of a powder or granule. It is also preferred wherein in step(b), the aqueous solution of 2-nitro-4-methylsulfonylbenzoic acid ispassed through a column packed with activated carbon.

In a preferred embodiment, NMSBA solids are dissolved in water at a pHgreater than 2 and filtered to remove any insoluble material. Theresulting solution is contacted with powdered activated carbon at a pHof about 3 to 8 to remove phenolic, nitro, and nitrophenolic impurities.After further filtration, the resulting solution is further treatedunder alkaline conditions to hydrolyze nitro and dinitro analogueimpurities of NMSBA which may be present as a consequence of thesynthetic methodologies leading up to NMSBA. The solution is heated,preferably to about 90-95° C., the pH is adjusted to about 1 with anorganic/inorganic acids such as orthophosphoric, oxalic, formic, malic,muriatic, nitric, sulfuric but preferably sulfuric acid and allowed tocool to room temperature. The resulting crystalline NMSBA can befiltered, washed and dried.

According to the present invention there is also provided purified NMSBAproduced or producible by the process.

According to the present invention there is also provided a process forproducing mesotrione, which comprises removing impurities from NMSBA bythe process described above and then converting the resulting purifiedNMSBA to mesotrione. On known method to do this is to react the NMSBAwith 1,3-cyclohexanedione so as to produce mesotrione. Suitable generalprocesses are described, for example in EP 805 792, EP 805 791 and U.S.Pat. No. 6,218,579. Generally, the NMSBA will not react directly withthe dione at an acceptable rate, and so the NMSBA is first converted toa more reactive derivative, such as an acid halide or an anhydride. Onesuch route is to convert the NMSBA to the corresponding acid chlorideusing a chloride source such as thionyl chloride or preferably phosgene,and then react this acid chloride with 1,3-cyclohexanedione so as toproduce mesotrione. The reaction of the acid chloride and cyclohexanonecan, for example be carried out in the presence of a cyanide catalystand triethylamine, although other processes are also known. In suchprocesses, typically, the solvents are removed via distillation and theMesotrione is precipitated from the remaining reaction mixture through aseries of pH adjustment steps and isolated by filtration orcentrifugation. According to the present invention there is alsoprovided a method of avoiding the production of Ames-positive mesotrioneby using the above process to purify NMSBA which is then used to makethe mesotrione as described. According to the present invention there isalso provided Ames-negative mesotrione produced or producable by thisprocess.

The following examples are to illustrate the invention but should not beinterpreted as a limitation thereon.

EXAMPLE 1

This example illustrates a “one pot” purification process of2-nitro-4-methanesulfonylbenzoic acid.

A 1L round bottom glass reactor equipped with an agitator, paddle,thermometer, heating mantle, condenser, pH electrode and 100 ml droppingfunnel, was charged with 360 ml water followed by 100 g NMSBA powder toform a slurry under moderate agitation. The mixture was charged 56 g ofcaustic at a rate of about 2 mL per minute to dissolve the solids.Allowed the mixture to agitate for 30 minutes until all the solids aredissolved to form milky white mixture at pH 3.65.

The resulting mixture was filtered through a #4 Whatman filter paper ina Buchner funnel under 50 mm Hg vacuum to give a clean light ambermother liquor. The mother liquor was filtered again through a #5 Whatmanfilter paper in a Buchner funnel under vacuum. The mother liquor wasreturned to the reactor and 10 g of Calgon activated carbon 2PG 10×40was added. The mixture was stirred moderately to prevent carbonattrition for 2 hours at 30° C. The carbon mixture was filtered at pH4.0 through a #4 and #5 Whatman filters, respectively to remove spentcarbon and residual carbon fines.

The clear mother liquor was returned to the 1 litre reactor and chargedwith 7.1 g of 25% NaOH to raise pH from 4.1 to 13.0. The darker alkalinemixture was allowed to agitate moderately at 30° C. for 1.5 hours tohydrolyze the overnitrated NMSBA analog impurities.

The mixture was acidified at ambient temperature by charging 5.1 gramsof 40% H₂SO₄ from pH 13 to pH 3.6 and started heating to 90° C. When thetemperature was at 90° C. the mixture was acidified further from pH 3.6to pH 0.8. The solution was cooled slowly to 60° C. and then under anice bath to ambient temperature, 25° C.

The resulting slurry was filtered through a Buchner funnel with #4Whatman filter paper. The cake was washed twice with 300 mL of tap waterand dewatered. About 112.5 g of wet solids were isolated from themixture. The solids were then dried in a vacuum oven at 60° C. overnightto result in 90 g of light amber powder. The purification yield was94.7%. The material was converted to Mesotrione which exhibited anegative Ames test.

EXAMPLE 2

One Pot Integrated Process—Effect of Carbon

This example illustrates the “one pot” integrated process to purify2-nitro-4-methanesulfonylbenzoic acid (NMSBA).

To a 2L round bottom glass reactor with agitator paddle, heating mantlecondenser, thermometer was charged 902 ml of water and 100 grams ofcrude NMSBA to form a slurry. To the slurry was charged 61 g of 25% NaOHsolution to pH 3.7. The mixture was filtered through a Buchner funnelwith #4 Whatman filter paper and a white residue was collected on thefilter paper. The filtrate was filtered again through a #5 Whatmanfilter paper. The clear mother liquor was split in two equal fractions.To one fraction was charged 5 g of activated carbon and none to theother.

The fraction with carbon was stirred for 2 hours at ambient temperatureat pH 3.7 and then filtered thought a #4 and #5 Whatman filter paper inBuchner funnel. The mother liquor was returned to the reactor andcharged 90 g of 25% NaOH solution to pH 13 and raised the temperature to90° C. for a few minutes. To the hot mixture was charged 175 ml of 40%sulfuric acid to pH 0.8 and cooled slowly to crystallize the mixture.The slurry was filtered and the solids washed and dried.

The pH of the second fraction (no carbon) was raised from 3.7 to 13within 92 grams of 25% NaOH solution and heated to 90° C. for a fewminutes. To the hot mixture was added 180 g of 40% sulfuric acid tolower the pH from pH 13 to 0.8. The mixture was then cooled slowly tocrystallize the product. The NMSBA solids for the fractions wereisolated by filtration through a Buchner funnel with #4 Whatman filterpaper. The filter cake was washed 2×100 of tap water and dewatered. Thewet cake was dried in a vacuum oven at 60° C. for 4 hrs. The fractionwith carbon afforded 43.2 grams of dry NMSBA and the fraction withoutcarbon 44.3 grams. These represent a recovery yield of 92 and 94%respectively in relation to crude NMSBA. The purified NMSBA materialsfrom the fractions were converted to Mesotrione product and tested foractivity in the Ames test. These resulted with an Ames negativeresponse.

EXAMPLE 3

This example illustrates purification process of2-nitro-4-methanesulfonylbenzoic acid by the procedure described inExample 2. This was done under various NMSBA product loading in relationto initial charge of 20, 30, and 50% using the following stoichiometry:

NMSBA Loading Example A B C Materials: 20% 30% 40% Crude NMSBA (90%), 3590 110 grams Tap Water 142 210 267 25% NaOH, grams (pH 22 78 70.4 3.5)25% NaOH, grams (pH 6.2 70 13) 40% H₂SO₄, grams 29 183 214 ActivatedCarbon, grams 4 9.0 10.7 (Calgon 10 × 40)

The resulting batches gave 28, 74 and 90 g of NMSBA product for the 20,30 and 40% solids loading. The NMSBA was analyzed and showed assaysranging from 99-100% by HPLC area % without detection of outstandingimpurities. The technical yields for batches ranging from 89 to 91% inrelation to the starting crude NMSBA. This material was converted toMesotrione which exhibited a negative Ames test.

EXAMPLE 4

Double Isolation Process

This example illustrates the purification of2-nitro-4-methylsulfonylbenzoic acid by a “double” isolation process.

1^(st) Isolation:

The 2-nitro-4-methylsulfonylbenzoic acid crude material was firsttreated by the procedure described in Example 1, with the processingsteps consisting of dissolution, filtration of insoluble impurities,hydrolysis, crystallization, isolation and drying.

2^(nd) Isolation:

To a 5 litre round bottom agitated reactor equipped with thermometer,heating mantle, condenser, pH electrode and 500 ml dropping funnel, 206g of 2-nitro-4-methylsulfonylbenzoic acid solids and 1800 g of waterwere added to form a slurry. Next, 125 g of 25% NaOH solution was addedvia dropping funnel to dissolve the solids at pH 3.5. The resultingmixture was filtered twice through a Buchner funnel equipped with 2.5micron Whatman #5 filter paper to result in 2172 grams of clear filtratewith pH of 3.5.

The resulting sodium salt solution of the2-nitro-4-methylsulfonylbenzoic acid was split in two equal fractions of1086 g each. The Fraction (A) was charged with 33 g of activated carbon,heated to 90° C. by charging 210 ml of 40% sulfuric acid solution slowlyvia a dropping funnel to pH 0.9. At this pH the mixture formed a slurrywith large crystals.

The Fraction (B) mixture was contacted with 10 g of activated carbon forone hour at ambient temperature under moderate agitation and allowed tosit overnight before removing spent carbon by filtration through a 40micron fritted glass funnel. The filtrate was crystallized at ambienttemperature by charging 195 mL of 40% sulfuric acid solution slowly viadropping funnel at pH 0.89. At this pH the mixture formed a slurry withslightly smaller crystals than fraction (A).

The resulting slurries from (A) and (B) fractions were filteredseparately through a Buchner funnel equipped with #4 Whatman filterpaper. The wet cake from each filtration was washed twice with 300 ml oftap water, dewatered and dried in a vacuum oven overnight at 40° C. The(A) and (B) fractions gave 90 and 88 g of purified2-nitro-4-methylsulfonylbenzoic acid, respectively. These fractions wereconverted to Mesotrione which exhibited negative Ames test response.

EXAMPLE 5

The sodium salt solution of NMSBA that has already been subjected to thefirst isolation as described in Example 1 is prepared by charging 2,700grams of water and 300 g of NMSBA to a 51 round bottom glass agitatedreactor at ambient temperature to form a slurry, followed by addition of187 g of 25% NaOH solution via dropping funnel to pH of 3.2±0.1 to forma clear mixture. Agitation is continued at a moderate rate at ambienttemperature (20-25° C.). This solution is filtered (350 g of thissolution) at pH 3.2 through a Buchner funnel equipped with #5 Whatmanfilter paper (2.5 micron) with vacuum at ambient temperature 20-25° C.The mother liquor is then charged (pH 3.2) to a 1L reactor equipped withan agitator with Teflon® paddle, thermometer, I²R Therm-o-Watchcontroller, heating mantle and condenser. The mixture is heated at 90°C. for 5-10 minutes under moderate agitation.

To this mixture is added 10.0 g of activated carbon to the hot mixtureand agitate for 1 hr at 90° C. (optional). The agitation is then stoppedand the mixture is filtered through a medium porosity Kimax frittedglass funnel at 90° C. with vacuum to remove the carbon. The carbon isrinsed twice with 25 ml of tap water.

The filtrate is then returned to the reactor and the temperature israised to 90° C. To the reactor is charged 40% H₂SO₄ solution slowly toadjust pH of the mixture from 3.2 to 1.0±0.2 followed by cooling slowlyto 60° C. NMSBA crystals should start forming at about 85° C. Cooling iscontinued under a cold water or ice bath from 60° C. to 20-25° C.

The slurry is then filtered through a Buchner Funnel with #4 Whatmanfilter paper and the wet solid cake is washed twice with 100 ml of tapwater. The solids are then dried in a vacuum oven at 60° C. for 8 hours.

1. A method for removing impurities from 2-nitro-4-methylsulfonylbenzoicacid which comprises the following steps, (a) dissolving2-nitro-4-methylsulfonylbenzoic acid in water at a pH of about 2 to 10,followed by filtration; (b) contacting an aqueous solution of2-nitro-4-methylsulfonylbenzoic acid with activated carbon at a pH ofabout 2 to 10; (c) treating an aqueous solution of2-nitro-4-methylsulfonylbenzoic acid with sufficient base to hydrolyzeundesired nitro and dinitro substituted impurities; followed bymaintaining the resulting aqueous solution comprising2-nitro-4-methylsulfonylbenzoic acid at a temperature of up to about 95°C., and adjusting the pH of said solution to about a pH which issufficient to effect crystallization of 2-nitro-4-methylsulfonylbenzoicacid upon cooling; wherein in said method, the method steps (a) and (b)are utilized, in any order; or wherein steps (b) and (c) are utilized,in any order; or wherein steps (a), (b) and (c) are utilized, in anyorder; or wherein steps (a), (b) and (c) are utilized in order.
 2. Themethod of claim 1, further comprising the step of washing saidcrystalline 2-nitro-4-methylsulfonylbenzoic acid with solvent, andoptionally drying said crystalline 2-nitro-4-methylsulfonylbenzoic acid.3. The method of claim 1, wherein in step (a), the base is selected fromthe group consisting of potassium hydroxide, calcium hydroxide, ammoniumhydroxide, sodium carbonate, and sodium bicarbonate.
 4. The method ofclaim 1, wherein in step (b), the activated carbon is in the form of apowder or granule.
 5. The method of claim 1, wherein in step (b), theaqueous solution of 2-nitro-4-methylsulfonylbenzoic acid is passedthrough a column packed with activated carbon.
 6. A process for makingmesotrione comprising purifying 2-nitro-4-methylsulfonylbenzoic acidaccording to the method of claim 1, and converting this purified2-nitro-4-methylsuIfonylbenzoic acid to mesotrione.
 7. The process ofclaim 6, in which the purified 2-nitro-4-methylsulfonylbenzoic acid isconverted to mesotrione by reaction with 1,3-cyclohexanedione.
 8. Theprocess of claim 7, in which the purified2-nitro-4-methylsulfonylbenzoic acid is first converted to thecorresponding acid chloride which is then reacted with1,3-cyclohexanedione.